Search Results (4,805)

The reliability of the characteristics of high-voltage (HV) thyristors is related to the operational safety of the entire HVDC project. In order to investigate the degradation mode of thyristors in HVDC projects more realistically, aging experiments were conducted on HV thyristors under the combined action of sinusoidal half-wave voltage and current in a simulated operating environment. Experimental results show that the on-state voltage, reverse recovery characteristics, and reverse leakage current of thyristors have all degraded to varying degrees during the aging process. The main failure mode of thyristors can be summarized as the failure of the reverse blocking characteristic. Microstructural characterization of failed HV thyristors is conducted to explain the degradation mechanisms, including device surface morphology and elemental composition analysis. Observations have shown that the failed thyristor silicon wafer has been burned and hollowed out, accompanied by copper impurities, and significant thermal breakdown has occurred at the edge of the anode surface of the chip. Defects in chip structure and the invasion of impurities can lead to a decrease in the minority carrier lifetime of materials, which is an important factor in the characteristics of semiconductor devices. On this basis, further simulation research is carried out to conclude that the shortening of the minority carrier lifetime of the thyristor will distort the carrier space distribution, resulting in the rise in the on-state voltage. Meanwhile, the carrier transport capability decreases, leading to a decrease in the reverse recovery speed. The energy released during the rapid generation and recombination of carriers is one of the main reasons for the failure of blocking characteristics. This work provides comprehensive insights into the failure modes and mechanisms of HV thyristors. Full article

Background/Objectives: Natural compounds occupy a pharmacologically rich chemical space, characterized by abundant scaffolds, extensive functional group elaboration, and defined stereochemistry. In this context, Helichrysum italicum, a Mediterranean medicinal plant, represents a valuable source of polyphenols with multiple biological and pharmacological activities. Methods: Here, we introduce an inverse molecular docking fingerprint approach to systematically investigate eight major Helichrysum italicum polyphenols, including $\alpha$-pyrones (arzanol, ethylpyrone), flavonols (gnaphaliin, kaempferol, quercetin), and flavanones (naringenin, pinocembrin, hesperetin). More than 40,000 human protein structures from the Protein Data Bank were screened to generate target-based inverse docking score fingerprints for each compound. Results: Hierarchical clustering of these fingerprints revealed shared binding patterns among structurally related polyphenols and enabled hypothesis generation regarding potential synergistic effects. Notably, favorable interactions were identified with PPARG and CARM1, supporting therapeutic relevance in inflammation and cancer, alongside additional targets associated with neurodegeneration and bone metabolism. Conclusions: This study establishes inverse docking fingerprints as a robust, mechanism-oriented method for natural product research and highlights Helichrysum italicum polyphenols as starting points for medicinal chemistry and drug discovery. Full article

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a key enzyme for the repair of stalled topoi-somerase 1 (TOP1)-DNA complexes. We have previously developed a TDP1 inhibitor, compound OL9-116, which is capable of enhancing the action of the anticancer drug topotecan (TPC), a TOP1 poison, in vitro and in vivo. In this study, the inhibition mode of OL9-116 (uncompetitive) was investigated. We have shown that N-terminal domain of TDP1, which is important for the cell function of TDP1 but is not involved in catalysis directly, reduced the inhibitory potency of OL9-116 probably by influencing the conformation of the enzyme. OL9-116 did not reduce cell viability and did not affect mitochondrial membrane potential. OL9-116 enhanced the cytotoxic/antiproliferative effect of TPC on the panel of tumor cells. This effect was not observed on nontumor cells or TDP1-deficient cells. OL9-116 and TPC had different effects on TDP1 and TOP1 gene expression detected by PCR depending on the cell type and the presence of functional TDP1. The direct relation between the effects of the compounds on the gene expression and cell survival was not found. The obtained data indicated a synergistic effect of OL9-116 and TPC, which appeared to be mediated by TDP1 inhibition rather than by an effect on TDP1 gene expression. Full article

Background: The COVID-19 pandemic triggered unprecedented mobility disruptions worldwide as governments imposed strict lockdowns to contain the spread of the virus. In India, prolonged restrictions severely affected economic activity, particularly for migrant workers, leading to a large-scale and unplanned exodus from urban employment centres to native places. This sudden population movement undermined containment efforts and contributed to the spatial diffusion of infections. Understanding evacuees’ behavioural responses during such crises is therefore critical for effective emergency logistics and evacuation planning. Methods: This study examines the determinants of transport mode and shelter choice decisions made by migrants during the COVID-19-induced evacuation in India. Using primary survey data, a multinomial logistic regression model is developed to analyze how socio-economic characteristics influence evacuees’ choices of travel mode and shelter type. Results: The results reveal significant heterogeneity in decision-making, highlighting the role of economic vulnerability and accessibility constraints in shaping evacuation behaviour. Conclusions: The findings offer actionable insights for policymakers and emergency planners to design inclusive evacuation strategies, improve crisis-responsive transportation planning, and enhance shelter provisioning in future pandemics or large-scale disruptions. The study contributes to the logistics and humanitarian operations literature by providing empirical evidence on evacuation behaviour under public health emergencies. Full article

A novel ocellatin-P1 isoform was isolated and purified from the skin secretion of the pepper frog Leptodactylus labyrinthicus. The crude skin secretion was fractionated by reversed-phase high-performance liquid chromatography (RP-HPLC) using a C₈ column and the peptide was subsequently purified on a reversed-phase C₁₈ column. Ocellatin-LB3 (as this isoform was named) was chemically sequenced by Edman degradation. This peptide is a linear C-terminally amidated molecule composed of 25 amino acid residues: ¹GLLDTLKGAAKNVVGGLASKVMEKL²⁵-NH₂. Synthetic ocellatin-LB3 was active against Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa and inactive against Staphylococcus aureus, Staphylococcus epidermidis and Enterococcus faecalis. In addition, the peptide reduced the Trypanosoma cruzi infection in L6 cells. At 64 µM it did not reduce erythrocytes or polymorphonuclear leukocytes, but did reduce mononuclear leukocyte counts, as detected by flow cytometry. No hemolytic activity was observed in red blood cells even at 128 µM. The peptide exhibited limited antiproliferative activity against MCF-7 and HeLa tumor cells at 128 µM. Pre-incubation with the peptide appeared to enhance N-formylmethionine-leucyl-phenylalanine (fMLP)-induced migration, indicating a potential additive or synergistic effect on human neutrophils. The three-dimensional structure of ocellatin-LB3 was investigated by circular dichroism (CD) and nuclear magnetic resonance (NMR). In the presence of sodium dodecyl sulfate (SDS), the peptide adopts an α-helical structure spanning residues Leu³–Lys²⁴, which remains largely preserved even at 95 °C. NMR Hydrogen/Deuterium (H/D) exchange experiments suggest that ocellatin-LB3 adopts a preferential orientation when interacting with SDS micelles. Based on the similarity among ocellatins, and on the physicochemical and structural properties of this peptide, a possible membrane-mediated mode of action is proposed, although this remains to be experimentally validated. Full article

Lactic Acid Bacteria (LAB)-derived antimicrobial compounds are recognized as a promising source of novel antimicrobial agents, particularly for the treatment of Methicillin-Resistant Staphylococcus aureus (MRSA), where the mode of action and associated cellular effects remain largely unexplored. This study aims to evaluate antibacterial activity of Limosilactobacillus fermentum YTPP05 isolated from pickled radish against MRSA. Upon the initial antibacterial evaluations, it was found that strain YTPP05 inhibited the growth of MRSA isolates. Multiplex PCR identified multiple resistance genes in our MRSA strains, including mecA, blaZ, and aacA genes, aligning with antibacterial susceptibility profiles determined by the disc diffusion assay. An agar overlay assay showed that YTPP05 possessed antibacterial potential, with the largest inhibition zone diameters of 40.83 ± 8.43 mm, while the inhibition zones of the Cell Free Supernatant (CFS) of YTPP05 by an agar well diffusion were 27.16 ± 2.93 mm against the MRSA isolates. The minimum inhibitory concentration and minimum bactericidal concentration of YTPP05-derived CFS were 125 mg/mL. Scanning Electron Microscopy (SEM) demonstrated YTPP05 extracts caused cell membrane disruption, bubble-like protrusion, and cell lysis. Collectively, this study highlights the anti-MRSA potential of YTPP05 as an alternative antimicrobial agent for combating MRSA infections. Full article

Bioactive glass (BAG) S53P4 is a clinically approved bone substitute with antibacterial, osteoconductive and osteostimulatory properties. Its antibacterial effect is associated with ion release, local pH elevation and osmolality, but the precise biochemical and biophysical mode-of-action is unclear. This study investigates the antibacterial mechanism of BAG S53P4 eluates. BAG eluates, collected at 2, 4, 8, and 24 h, eradicated Staphylococcus aureus. Elemental analysis revealed an early increase in concentrations of Si and Na, a later rise in Ca, depletion of P over time and rapid loss of Mg. Membrane disturbances occurred within 5 min, evident by permeability for SYTOX, aligning with time-kill kinetics for S. aureus and Bacillus subtilis. In B. subtilis, 2h-BAG-eluate induced rapid delocalization of marker proteins for cell division and DNA repair, signaling membrane potential collapse and nucleoid condensation. Transcriptomics revealed early transcription remodeling reflecting ionic and energetic imbalance, including disruption of central metabolism, redox homeostasis, and translational stability. Scanning electron microscopy revealed severe cell surface damage and particulate deposits on S. aureus. Transmission electron microscopy showed cell envelop disruptions and cytoplasmic leakage. Energy dispersive X-ray analysis identified Si on bacterial cell surface at 4 h and intracellular accumulation in punctured, empty cells at 24 h. Overall, BAG ionic dissolution products kill bacteria through a stepwise mechanism involving membrane damage, protein delocalization and metabolic impairment, accompanied by Si deposition on bacterial surfaces and loss of Mg. This finally leads to cell wall degradation, cytoplasmic content leakage and further Si deposition on the cells and inside cell ghosts. Full article

Background/Objectives: Developing novel strategies to combat respiratory infections caused by multidrug-resistant “priority pathogens” like the ESKAPEE Pseudomonas aeruginosa and Staphylococcus aureus is an urgent priority. Methods: We investigated two shortened variants of the proline-rich antimicrobial peptide (PrAMP) B7-005, B7-006 (15-mer) and B7-007 (13-mer). Evaluation included MIC assays against laboratory and clinical multidrug-resistant isolates, mechanistic studies of membrane permeabilization, cytotoxicity testing on BEAS-2B bronchial epithelial cells, and proteolytic stability assays in human elastase and sputum. Results: Despite their reduced size, lower positive charge, and decreased proline content, both variants retained full antimicrobial activity against clinical pathogens with consistent MIC values ≤ 25 µM. These variants exhibit membrane permeabilization in P. aeruginosa but may also relay on a hybrid mode of action involving also intracellular targets. Notably, B7-006 and B7-007 displayed low cytotoxicity compared to the lytic peptide BMAP-18. While B7-007 showed greater susceptibility to proteolytic degradation than its parent B7-005, it preserved partial integrity during the initial hours of exposure. Conclusions: Overall, these findings demonstrate that the B7 scaffold tolerates substantial truncation while preserving potency and selectivity, identifying a minimal 13-amino-acid active core. This work provides critical insights into structure–activity relationships and supports the development of compact, mechanistically versatile antimicrobial peptides to address the growing threat of multidrug-resistant respiratory pathogens. Full article

Background: Dental caries remains one of the most prevalent oral diseases worldwide, largely driven by the virulence of Streptococcus mutans. Although plant phenolics from green tea and pomegranate are known for their antimicrobial properties, their molecular mechanisms of action against key S. mutans virulence targets remain insufficiently characterized. Aim: This study investigated the antibacterial and anti-virulence properties of Viroelixir, a phenolic-rich formulation derived from green tea (Camellia sinensis) and pomegranate (Punica granatum), against S. mutans, with particular emphasis on predictive molecular docking interactions with critical virulence-associated proteins. Methods: Viroelixir phytochemical composition was characterized by LC–MS using a C18 reverse-phase column and negative electrospray ionization mode. Antibacterial activity was evaluated using growth kinetics, agar plating, and crystal violet assays. Acidogenicity, hemolytic activity, and biofilm formation were assessed using pH modulation, hemolysis assays, SEM, and biofilm biomass quantification. Virulence gene expression was analyzed by RT-qPCR. In silico molecular docking was performed to explore potential interactions between major LC–MS-supported phenolic constituents and S. mutans virulence proteins, including glucosyltransferase B (GtfB), LuxS, and SpaP. Biocompatibility was evaluated in human gingival epithelial cells. Results: The LC-MS analysis revealed a complex mixture of phenolic compounds consistent with catechins and ellagitannins. Compound identification was considered tentative and based on mass spectral range and chromatographic behavior. Viroelixir significantly inhibited S. mutans growth, acid production, hemolytic activity, and biofilm formation in a concentration-dependent manner. Key virulence genes were markedly downregulated. Docking analyses suggested stable binding of selected phenolics—particularly punicalagin, catechin, and epigallocatechin—within the active sites of GtfB, LuxS, and SpaP. Importantly, Viroelixir showed no cytotoxic effects on gingival epithelial cells. Conclusions: Viroelixir exerts potent antibacterial and anti-virulence effects against S. mutans through a multi-target mechanism combining transcriptional suppression and predictive molecular inhibition of virulence proteins, supporting its potential as a safe, natural therapeutic for caries prevention. Full article

In the Vaibhāṣika system, possession (prāpti), classified as a factor that is neither material nor mental, is posited as a real entity that links the various dharmas associated with a sentient being to its individual continuum. In this context, possession does not refer to legal ownership or supernatural possession; rather, it refers to the attainment or endowment of dharmas, that is, how particular qualities, actions, or mental states come to be present in a given individual. This paper examines the strategies by which Vaibhāṣikas defend the ontological status of possession, thereby shedding light on the motivations underlying this doctrinal commitment. Through close philological and historical analysis of a wide range of Sarvāstivāda Abhidharma sources, including passages from a newly available manuscript folio of the Abhidharmadīpa with Vibhāṣāprabhāvṛtti, this study reconstructs the diachronic development of Vaibhāṣika arguments for the real existence of possession. Vaibhāṣikas consistently employ two principal modes of justification: appeals to scriptural authority (āgama) and logical reasoning (yukti). As the tradition develops, their defenses of possession shift from reliance on scriptural sources toward increasingly sophisticated forms of doctrinal and functional integration. Possession thus evolves from a dharma serving to clarify specific doctrinal difficulties into a structurally embedded component of Vaibhāṣika doctrinal architecture, playing an important role in its accounts of soteriology, causality, and karma. Full article

Honey lemon (H&L) is a traditional beverage known for its potential liver-protective effects, but its mechanisms against alcoholic liver disease (ALD) remain poorly understood. This study aimed to investigate the hepatoprotective properties of H&L and explore its multi-target mechanisms in alleviating ALD. Using network pharmacology and molecular docking, we identified 26 bioactive compounds in H&L and 335 potential targets associated with ALD. Pathway enrichment analysis revealed that H&L might exert its influence by regulating inflammation, oxidative stress and ethanol metabolism. Molecular docking further demonstrated strong binding interactions between key flavonoids (hesperidin, diosmin, and eriocitrin) and crucial targets, such as AKT1, SRC, STAT3, as well as ethanol-metabolizing enzymes like ADH, ALDH, and CYP2E1. In vivo experiments suggested that H&L alleviated liver injury and significantly improved selected indicators related to ethanol metabolism, oxidative stress, and inflammatory response. For several variables, including ALT/AST, ALDH, IL-6, and hepatic ethanol content, improvement trends were observed, although not all differences reached statistical significance. Overall, the results suggest that the protective effect of H&L against ALD may be associated with a multi-component, multi-target, and multi-pathway mode of action, supporting its potential for further investigation as a functional food candidate. Full article

Acute kidney injury (AKI) presents a critical clinical challenge due to its rapid progression and lack of effective targeted therapies. The herbal combination of rhubarb and Salvia miltiorrhiza, a cornerstone of Traditional Chinese Medicine (TCM) for renal protection, shows promise, yet its bioactive components and mode of action remain incompletely understood. This study identifies and characterizes inherent nanoscale entities from this herbal pair as a novel nanotherapeutic platform. Self-assembled nanoparticles (designated RSNPs) were isolated from the ethanol extract via differential centrifugation. Comprehensive characterization revealed that RSNPs form stable nanostructures through spontaneous self-assembly, primarily driven by supramolecular interactions (e.g., π-π stacking and hydrogen bonding). UPLC-MS/MS quantification confirmed the co-assembly of multiple bioactive constituents within RSNPs. Network pharmacology and molecular docking initially predicted their synergistic action on AKI-related pathways. In a cisplatin-induced murine AKI model, RSNP administration markedly attenuated renal dysfunction and histopathological damage, mechanistically linked to the mitigation of oxidative stress (e.g., decreased MDA and increased SOD) and inflammation (e.g., downregulated TNF-α and IL-6). In vitro, RSNPs demonstrated enhanced cellular internalization and superior cytoprotection against cisplatin toxicity in renal tubular epithelial cells, significantly reducing apoptosis. These findings unveil that the therapeutic efficacy of the Rheum palmatum L.–Salvia miltiorrhiza Bunge pair is intrinsically embedded within its nanoscale architecture. RSNPs represent a new class of TCM-derived nanotherapeutics with a well-defined material basis and multimodal mechanisms, offering a promising strategy for AKI treatment. Full article

Growing interest in environmentally compatible stored-product pest control has highlighted diatomaceous earth (DE) and 1,8-cineole as promising agents, both alone and in combination. Their different modes of action, together with the limitations associated with higher-dose single applications, support evaluating their combined use at lower doses. This study was conducted to compare the effects of DE and 1,8-cineole, applied alone and in combination, on the larval, pupal, and adult stages of Tenebrio molitor. Five different concentrations were tested for each substance (DE at 25, 50, 100, 250, and 500 ppm, and 1,8-cineole at 2.5, 5, 10, 15, and 20 ppm), and four DE + 1,8-cineole combinations were evaluated within the same experimental system. Mortality was monitored over time, LC₅₀ values were calculated by probit analysis, and larval output observed after adult treatments was also evaluated. The findings indicated that the biological response was associated with developmental stage. The lowest LC₅₀ for DE was recorded in larvae at 86.11 ppm on day 3, whereas for 1,8-cineole the lowest LC₅₀ was recorded in adults at 94.83 ppm on day 3. Combined treatments generally tended to produce faster and stronger mortality; in particular, the DE250 + CIN20 treatment reached 100% mortality in larvae and adults and 93.33% mortality in pupae by day 7. In addition, larval output decreased in the single-treatment groups, the proportion of dead larvae among the observed larvae increased to 96–100%, and no larval output was detected in the combination groups. Combinations of DE and 1,8-cineole tended to produce more pronounced mortality responses than the single treatments, particularly in the larval and adult stages. The present findings indicate that combining DE with 1,8-cineole may provide a promising stage-specific strategy for improving the control of T. molitor under laboratory conditions. Full article

Interactions between the gut microbiota, immune system, and brain seem to be involved in the pathogenesis and disease activity of multiple sclerosis (MS). Some MS disease-modifying therapies (DMTs) have been shown to alter the microbiota, but whether this is related to their specific mode of action or indirectly related to their immune-modulatory effect is unknown. In this longitudinal study, we characterized the effects of two DMTs on the microbiota under similar conditions and populations: the injectable, moderate-efficacy DMT interferon beta-1a (INFβ-1a) and the oral, high-efficacy DMT cladribine tablets (CladT). Taxonomic differences were identified following 6 months of therapy for each DMT, and both were associated with the elevation of short-chain fatty acid (SCFA) producers from the Lachnospiraceae, Lactobacillaceae, and Ruminococcaceae families (Firmicutes), while members of Bacteroidetes and Proteobacteria were reduced. Moreover, a higher abundance of Alphaproteobacteria and Betaproteobacteria at baseline was associated with disease activity within 1–2 years of follow-up, while a higher abundance of Lachnospiraceae, Ruminococcaceae, Bifidobacteriaceae, and Streptococcaceae microbes, among others, was associated with no evidence of disease activity (NEDA). Our results provide supporting evidence that alteration of the microbiota by DMTs is part of their beneficial effect, and while some modifications seem to be DMT-specific, MS-DMTs in general promote SCFA-producing microbes, which positively correlate with a favorable clinical outcome. Future therapeutic strategies for PwMS may benefit from microbiome modulation, contingent upon additional mechanistic and interventional studies. Full article

To enhance the dynamic response and robustness of permanent magnet synchronous motor (PMSM) speed regulation under load disturbances, this study proposes a composite control strategy that integrates a novel sliding mode control based on an adaptive reaching law (NSMC) with a high-order disturbance observer (HDOB). First, an adaptive reaching law is designed to accelerate the convergence process when the system state is far from the sliding surface, while an adaptive saturation function (ASF) is introduced to smooth switching actions and reduce chattering near the sliding surface. Subsequently, a high-order disturbance observer is developed to estimate the lumped disturbance and its variation in real time, with the estimated disturbance being fed forward to the output of the speed-loop controller to enhance disturbance rejection capability. The effectiveness of the proposed method is validated through simulations and real-time experiments on a Hall-sensor-based PMSM drive platform. Experimental results show that, at a reference speed of 600 r/min, the proposed NSMC reduces settling time by 43.1% compared with conventional sliding mode control, while virtually eliminating overshoot. Under sudden load application and removal, the proposed NSMC + HDOB reduces the maximum speed deviation by 38.3% and 57.2%, respectively, compared with SMC + HDOB. These results indicate that the proposed strategy achieves faster speed tracking, smaller speed fluctuations, and enhanced robustness against load disturbances, offering an effective solution for high-performance PMSM drive systems. Full article